Abstract: This paper provides a comprehensive explanation of striated muscle mechanics and contraction on the basis of filament rotations. Helical proteins, particularly the coiled-coils of tropomyosin, myosin and α-actinin, shorten their H-bonds cooperatively and produce torque and filament rotations when the Coulombic net-charge repulsion of their highly charged side-chains is diminished by interaction with ions. The classical “two-component model” of active muscle differentiated a “contractile component” which stretches the “series elastic component” during force production. The contractile components are the helically shaped thin filaments of muscle that shorten the sarcomeres by clockwise drilling into the myosin cross-bridges with torque decrease (= force-deficit). Muscle stretch means drawing out the thin filament helices off the cross-bridges under passive counterclockwise rotation with torque increase (= stretch activation). Since each thin filament is anchored by four elastic α-actinin Z-filaments (provided with forceregulating sites for Ca2+ binding), the thin filament rotations change the torsional twist of the four Z-filaments as the “series elastic components”. Large scale models simulate the changes of structure and force in the Z-band by the different Z-filament twisting stages A, B, C, D, E, F and G. Stage D corresponds to the isometric state. The basic phenomena of muscle physiology, i. e. latency relaxation, Fenn-effect, the force-velocity relation, the length-tension relation, unexplained energy, shortening heat, the Huxley-Simmons phases, etc. are explained and interpreted with the help of the model experiments.

Abstract: The mechanics of the actomyosin interaction is central in muscle contraction and intracellular trafficking. A better understanding of the events occurring in the actomyosin complex requires the examination of all nucleotide-dependent states and of the energetic features associated with the dynamics of the cross-bridge cycle. The aim of the present study is to estimate the interaction strength between myosin in nucleotide-free, ATP, ADP·Pi and ADP states and actin monomer. The molecular models of the complexes were constructed based on cryo-electron microscopy maps and the interaction properties were estimated by means of a molecular dynamics approach, which simulate the unbinding of the complex applying a virtual spring to the core of myosin protein. Our results suggest that during an ATP hydrolysis cycle the affinity of myosin for actin is modulated by the presence and nature of the nucleotide in the active site of the myosin motor domain. When performing unbinding simulations with a pulling rate of 0.001 nm/ps, the maximum pulling force applied to the myosin during the experiment is about 1nN. Under these conditions the interaction force between myosin and actin monomer decreases from 0.83 nN in the nucleotide-free state to 0.27 nN in the ATP state, and increases to 0.60 nN after ATP hydrolysis and Pi release from the complex (ADP state).

Abstract: Myofibrillogenesis in striated muscle cells requires a precise ordered pathway to assemble different proteins into a linear array of sarcomeres. The sarcomere relies on interdigitated thick and thin filaments to ensure muscle contraction, as well as properly folded and catalytically active myosin head. Achieving this organization requires a series of protein folding and assembly steps. The folding of the myosin head domain requires chaperone activity to attain its functional conformation. Folded or unfolded myosin can spontaneously assemble into short myosin filaments, but further assembly requires the short and incomplete myosin filaments to assemble into the developing thick filament. These longer filaments are then incorporated into the developing sarcomere of the muscle. Both myosin folding and assembly require factors to coordinate the formation of the thick filament in the sarcomere and these factors include chaperone molecules. Myosin folding and sarcomeric assembly requires association of classical chaperones as well as folding cofactors such as UNC-45. Recent research has suggested that UNC-45 is required beyond initial myosin head folding and may be directly or indirectly involved in different stages of myosin thick filament assembly, maintenance and degradation.

Abstract: Complete details of the thermodynamics and molecular mechanisms of ATP synthesis/hydrolysis and muscle contraction are offered from the standpoint of the torsional mechanism of energy transduction and ATP synthesis and the rotation-uncoiling-tilt (RUT) energy storage mechanism of muscle contraction. The manifold fundamental consequences and mechanistic implications of the unified theory for oxidative phosphorylation and muscle contraction are explained. The consistency of current mechanisms of ATP synthesis and muscle contraction with experiment is assessed, and the novel insights of the unified theory are shown to take us beyond the binding change mechanism, the chemiosmotic theory and the lever arm model. It is shown from first principles how previous theories of ATP synthesis and muscle contraction violate both the first and second laws of thermodynamics, necessitating their revision. It is concluded that the new paradigm, ten years after making its first appearance, is now perfectly poised to replace the older theories. Finally, applications of the unified theory in cell life and cell death are outlined and prospects for future research are explored. While it is impossible to cover each and every specific aspect of the above, an attempt has been made here to address all the pertinent details and what is presented should be sufficient to convince the reader of the novelty, originality, breakthrough nature and power of the unified theory, its manifold fundamental consequences and mechanistic implications, and its applications in health and disease.

Abstract: Mechanical energy from oxygen metabolism by mammalian tissues has been studied since 1837. The production of heat by mechanical work was studied by Fick in about 1860. Prior to Fick’s work, energetics were revised by Joule’s experiments which founded the First Law of Thermodynamics. Fenn in 1923/24 found that frog muscle contractions generated extra heat proportional to the amount of work done in shortening the muscle. This was fully consistent with the Joule, Helmholtz concept used for the First Law of Thermodynamics. The link between the energetics of water and ATP hydrolysis in molecular motors is recommended for reconsideration.

Abstract: We present a soft bio-machine constructed from biological motors (actin/myosin). We have found that chemically cross-linked polymer-actin complex gel filaments can move on myosin coated surfaces with a velocity as high as that of native Factin, by coupling to ATP hydrolysis. Additionally, it is shown that the velocity of polymer-actin complex gel depends on the species of polycations binding to the F-actins. Since the design of functional actuators of well-defined size and morphology is important, the structural behavior of polymer-actin complexes has been investigated. Our results show that the morphology and growth size of polymer-actin complex can be controlled by changes in the electrostatic interactions between F-actins and polycations. Our results indicate that bio actuators with desired shapes can be created by using a polymer-actin complex.

Abstract: Most bacteria that swim are propelled by flagellar filaments, which are driven by a rotary motor powered by proton flux. The mechanism of the flagellar motor is discussed by reforming the model proposed by the present authors in 2005. It is shown that the mean strength of Coulomb field produced by a proton passing the channel is very strong in the Mot assembly so that the Mot assembly can be a shear force generator and induce the flagellar rotation. The model gives clear calculation results in agreement with experimental observations, e g., for the charasteristic torque-velocity relationship of the flagellar rotation.

Abstract: Muscle contraction studies often focus solely on myofibres and the proteins known to be involved in the processes of sarcomere shortening and cross-bridge cycling, but skeletal muscle also comprises a very elaborate ancillary network of capillaries, which not only play a vital role in terms of nutrient delivery and waste product removal, but are also tethered to surrounding fibres by collagen ”wires”. This paper therefore addresses aspects of the ancillary network of skeletal muscle at both a microscopic and functional level in order to better understand its role holistically as a considerable contributor to force transfer within muscular tissue.

Abstract: The interaction between water and the protein of the contractile machinery as well as the tendency of these proteins to form geometrically ordered structures provide a link between water and muscle contraction. Protein osmotic pressure is strictly related to the chemical potential of the contractile proteins, to the stiffness of muscle structures and to the viscosity of the sliding of the thin over the thick filaments. Muscle power output and the steady rate of contraction are linked by modulating a single parameter, a viscosity coefficient. Muscle operation is characterized by working strokes of much shorter length and much quicker than in the classical model. As a consequence the force delivered and the stiffness attained by attached cross-bridges is much larger than usually believed.

Abstract: The sarcomere is the fundamental unit of cardiac and skeletal muscle contraction. During the last ten years, there has been growing awareness of the etiology of skeletal and cardiac muscle diseases originating in the sarcomere, an important evolving field. Many sarcomeric diseases affect newborn children, i. e. are congenital myopathies. The discovery and characterization of several myopathies caused by mutations in myosin heavy chain genes, coding for the major component of skeletal muscle thick filaments, has led to the introduction of a new entity in the field of neuromuscular disorders: myosin myopathies. Recently, mutations in genes coding for skeletal muscle thin filaments, associated with various clinical features, have been identified. These mutations evoke distinct structural changes within the sarcomeric thin filament. Current knowledge regarding contractile protein dysfunction as it relates to disease pathogenesis has failed to decipher the mechanistic links between mutations identified in sarcomeric proteins and skeletal myopathies, which will no doubt require an integrated physiological approach. The discovery of additional genes associated with myopathies and the elucidation of the molecular mechanisms of pathogenesis will lead to improved and more accurate diagnosis, including prenatally, and to enhanced potential for prognosis, genetic counseling and developing possible treatments for these diseases. The goal of this review is to present recent progress in the identification of gene mutations from each of the major structural components of the sarcomere, the thick and thin filaments, related to skeletal muscle disease. The genetics and clinical manifestations of these disorders will be discussed.

Abstract: Muscle contraction mechanism is discussed by reforming the model described in an article by Mitsui (Adv. Biophys. 1999, 36, 107-158). A simple thermodynamic relationship is presented, which indicates that there is an inconsistency in the power stroke model or the swinging lever model. To avoid this difficulty, a new model is proposed. It is assumed that a myosin head forms a polaron-like complex with about three actin molecules when it attaches to an actin filament and the complex translates along the actin filament producing force. Various experimental data on the muscle contraction are well explained based upon the model.

Abstract: Problems of quantitative investigation of intracellular diffusion and compartmentation of metabolites are analyzed. Principal controversies in recently published analyses of these problems for the living cells are discussed. It is shown that the formal theoretical analysis of diffusion of metabolites based on Fick’s equation and using fixed diffusion coefficients for diluted homogenous aqueous solutions, but applied for biological systems in vivo without any comparison with experimental results, may lead to misleading conclusions, which are contradictory to most biological observations. However, if the same theoretical methods are used for analysis of actual experimental data, the apparent diffusion constants obtained are orders of magnitude lower than those in diluted aqueous solutions. Thus, it can be concluded that local restrictions of diffusion of metabolites in a cell are a system-level properties caused by complex structural organization of the cells, macromolecular crowding, cytoskeletal networks and organization of metabolic pathways into multienzyme complexes and metabolons. This results in microcompartmentation of metabolites, their channeling between enzymes and in modular organization of cellular metabolic networks. The perspectives of further studies of these complex intracellular interactions in the framework of Systems Biology are discussed.

Abstract: Active streaming (AS) of liquid water is considered to generate and overcomepressure gradients, so as to drive cell motility and muscle contraction by hydrauliccompression. This idea had led to reconstitution of cytoplasm streaming and musclecontraction by utilizing the actin-myosin ATPase system in conditions that exclude acontinuous protein network. These reconstitution experiments had disproved a contractileprotein mechanism and inspired a theoretical investigation of the AS hypothesis, aspresented in this article. Here, a molecular quantitative model is constructed for a chemicalreaction that might generate the elementary component of such AS within the pure waterphase. Being guided by the laws of energy and momentum conservation and by the physicalchemistry of water, a vectorial electro-mechano-chemical conversion is considered, asfollows: A ballistic H+ may be released from H2O-H+ at a velocity of 10km/sec, carrying akinetic energy of 0.5 proton*volt. By coherent exchange of microwave photons during 10-10sec, the ballistic proton can induce cooperative precession of about 13300 electrically-polarized water molecule dimers, extending along 0.5 μm. The dynamic dimers rearrangealong the proton path into a pile of non-radiating rings that compose a persistent rowing-likewater soliton. During a life-time of 20 msec, this soliton can generate and overcome amaximal pressure head of 1 kgwt/cm2 at a streaming velocity of 25 μm/sec and intrinsicpower density of 5 Watt/cm3. In this view, the actin-myosin ATPase is proposed to catalyzestereo-specific cleavage of H2O-H+ , so as to generate unidirectional fluxes of ballisticprotons and water solitons along each actin filament. Critical requirements and evidentialpredictions precipitate consistent implications to the physical chemistry of water, enzymatichydrolysis and synthesis of ATP, trans-membrane signaling, intracellular transport, cellmotility, intercellular interaction, and associated electro-physiological function. Sarcomerecontraction is described as hydraulic compression, driven by the suction power of centrally-oriented AS. This hydraulic mechanism anticipates structural, biochemical, mechanical and energetic aspects of striated muscle contraction, leading to quantitative formulation of a hydrodynamic power-balance equation yielding a general force-velocity relation.